The goal of this program is the development of new physical and chemical techniques to solve previously intractable problems in cell and molecular biology. More than half the effort will be devoted to the refinement of pulsed field gradient gel electrophoresis and the development of highly specific methods for cleaving DNA molecules. Together these techniques will allow rapid mapping of human genes, and molecular analysis of various chromosome rearrangements including genes and rearrangements linked to oncogenic transformation. Part of the program will focus on the topological properties of chromatin in tumor virus minichromosomes and in whole mammalian chromosomes. The object is to understand how chromatin structure and energetics change during gene expression and how the stiffness of DNA is used in normal and abnormal gene regulation. Another part of the program deals with the internalization of macromolecules by lymphocytes. One objective is to study how particular lymphocytes are able to internalize particular histocompatibility antigens. Another objective is to develop systems that exploit lymphocyte internalization to deliver photoactivatable drugs to malignant lymphoctyes. Finally, in two very speculative projects techniques will be developed to probe for the existence of RNA topoisomers and other techniques will be developed to produce fluorescently labeled proteins biosynthetically.